Review Heterotopic ossi cation: a systematic review · the skeletal system to continuously adapt to...

Heterotopic ossification: a systematic reviewDafydd S Edwards,1 J C Clasper2

1Centre for Blast Injury Studies,Imperial College London,London, UK2Defence Professor of Trauma& Orthopaedics, AcademicDepartment of Military Surgeryand Trauma, RCDMBirmingham, UK

Correspondence toMaj Dafydd S Edwards,Centre for Blast Injury Studies,Imperial College London,South Kensington, LondonSW7 2AZ, UK;[email protected]

Received 27 March 2014Revised 25 May 2014Accepted 10 June 2014Published Online First11 July 2014

To cite: Edwards DS,Clasper JC. J R Army MedCorps 2015;161:315–321.

ABSTRACTHeterotopic ossification (HO) is the formation of maturelamellar bone in extraskeletal soft tissues. It was firstdescribed 1000 years ago in the healing of fractures,and in relation to military wounds, texts from theAmerican Civil War and World War I refer to HO specific-ally. It continues to cause problems to injured servicepersonnel; the consequences of wound and soft tissuecomplications in traumatic amputations pose particularproblems to rehabilitation and prosthetic use. While HOis seen in rare genetic conditions, it is most prevalentafter joint replacement surgery and trauma. In the civil-ian setting HO has been commonly described in patientsafter traumatic brain injuries, spinal cord injuries andburns. Militarily, as a consequence of recent operations,and the characteristic injury of blast-related amputations,a renewed interest in HO has emerged due to anincreased incidence seen in casualties. The heteroge-neous nature of a blast related amputation makes it diffi-cult for a single aetiological event to be identified,although it is now accepted that blast, amputationthrough the zone of injury, increased injury severity andassociated brain injuries are significant risk factors in HOformation. The exact cellular event leading to HO has yetto be identified, and as a consequence its prevention isrestricted to the use of anti-inflammatory medication andradiation, which is often contraindicated in the acutecomplex military casualty. A systematic review inPubMed and the Cochrane Database identified researcharticles related to HO to illustrate the military problem ofHO and its management, current research concepts andexperimental theories regarding HO. This also served asa gap analysis providing the researchers detail of anyknowledge deficit in this field, in particular to the mili-tary aspects of HO; 637 out of 7891 articles initiallyidentified that referenced HO were relevant to thisreview.

INTRODUCTIONHeterotopic ossification (HO) (Figure 1) is the for-mation of mature lamellar bone in extraskeletal softtissues. It was first described in the literature nearly1000 years ago in the healing of fractures,1 and inrelation to military wounds, and complications ofamputations, texts from the American Civil Warand World War I make specific reference to it.2 Todate HO continues to cause problems to theinjured service personnel3 4 with its consequencesposing particular difficulties to rehabilitation5 6 andlong-term prosthetic use.3

It can be classified into congenital or acquired;the latter usually being associated with trauma. Inthe military and the civilian settings traumatic braininjury (TBI) and traumatic amputations are recog-nised risk factors for HO7–9; despite these associa-tions the exact pathogenic mechanism remainselusive.

The prevalence of HO in the military setting isreported to be increasing.10 This is thought to bedue to increased survivorship of casualties withmore severe extremity injuries seen in recent opera-tions.11 In addition the characteristic mechanism ofinjury seen in operations in Afghanistan, and thelatter stages in Iraq, has been blast from improvisedexplosive devices (IEDs). Many studies have triedto identify causal factors from the mechanism ofinjury, management of wounds and complicationsand the subsequent formation of HO.4 9 Howeverwith so many variables involved in the formationand treatment of a complex military wound, it isdifficult to isolate a single aetiological event.Due to the injury severity of the casualty, and the

complexity and highly contaminated wounds,primary prevention is unlikely to be possible; there-fore the military surgeon is left with little in hisarmoury apart from surgical excision, after the for-mation of HO. Case series of individual depart-ment experiences in the management of HO areseen in the literature10 12 but there is no consistentmanagement consensus.Until recently research and evidence concerning

HO has been led by civilian academic departments,however the increased prevalence and functionalcompromise has driven the military requirementfor further work on its aetiology, structure, biology,prevention and treatment. To identify scientificneeds and future research directions, a systematicreview of literature related to HO was performed.

METHODSWe employed ‘PRISMA’ systematic review guide-lines; searching the PubMed database for referencesusing the search terms ‘heterotopic’ and ‘ossifica-tion’ as keywords, and limiting our search to thelast 100 years. Primary and secondary exclusion cri-teria were then used to filter the results (Table 1)after a secondary filter, further filtering, or the useof additional keywords, was found to over-refineour search and significant articles excluded.Therefore it was felt that further searches shouldbe done manually. Manual strategies employed toestablish relevance, in order of hierarchical import-ance, were (1) Title review, (2) MeSH term review,(3) Abstract review and finally (4) Full articlereview. A flow chart of the search is demonstratedin Figure 2. Relevant articles were subsequentlygrouped into related subjects (Table 2).

RESULTSInitially 7891 articles related to HO (Figure 3)were identified which was reduced to 637 afterrefining the search using the primary, secondaryand manual exclusion strategies. The number ofarticles published in the last 10 years increasedfrom 54 to 88, between 2003 and 2013. Three

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distinct groups of research were evident, elective surgery,trauma surgery and scientific basis of disease, representing 54%,25% and 21%, respectively, of the articles published. The mostcommon publication subject was that of HO related to hiparthroplasty (n=218, 34.2%). Only 26 articles were foundreferring to HO in the military trauma setting.

One limitation encountered in the systematic review was achange in nomenclature of HO. Terms such as ectopic bone for-mation, myositis ossificans and heterotopic ossification wereused interchangeably in history.

Normal bone formationPrerequisites for bone formation are inductive signalling path-ways, consisting of chemical mediators (chemokines and cyto-kines), including bone morphogenetic protein (BMP), plateletderived growth factors, fibroblast growth factors, prostaglandins(PGs) and interleukins, all of which trigger bone formation;inducible osteoprogenitor cells which are cells capable of beingdifferentiated into bone forming osteoblasts and finally an envir-onment conducive to osteogenesis (a scaffold for the deposition

of new bone).7 10 (Figure 4) In the normal physiological statethese prerequistes exist, together with osteoclast resorption, toallow a slow metabolic turnover of normal bone. This enablesthe skeletal system to continuously adapt to changes in normalphysiological loads, such as growth or increased physical activity

Scientific basis of diseaseGeneticsHO can be divided into congenital (or genetic) and acquired.Acquired causes are by far the most common; however, geneticcauses provide evidence of the genetic basis for the formationof HO. Two congenital conditions exist specifically related tothe formation of ectopic bone. Fibrodysplasia ossificans progres-siva (FOP) and progressive osseous hyperplasia are rare geneticconditions which result in severe disability secondary to exten-sive bone formation in all soft tissues.13 In FOP the exactmutated gene has yet to be identified and is usually a spontan-eous occurrence, but where familial tendency exists it seems toconfer an autosomal dominant pattern.14 In the early stages ofthe disease a lymphocyte-associated mechanism has been identi-fied thereby inferring an inflammatory pathogenic process.15

Geneticists have demonstrated that the expression of BMP-4, aninflammatory mediator, is significantly increased in cases ofFOP.16 The downregulation of Noggin, a BMP-4 antagonist hasalso been shown in FOP.17

An autosomal inheritance pattern is seen in progressiveosseous hyperplasia with the heterozygous inactivation of theGNAS1 gene exclusively inherited from the father.18 Thisresults in decreased expression of the stimulatory G protein ofadenylyl cyclase, another inflammatory mediator. BMP-4 andstimulatory G protein are associated with bone formation.

Pathological bone formationThe relevance of normal bone formation to pathological boneformation is summarised by Kirsch who states that the molecu-lar mechanisms that are normally found regulating physiologicalbone formation and turnover are present in pathological condi-tions of ectopic bone formation in the skeletal system, andextraosseous soft tissues such as cartilage, blood vessels andmuscles.19 How this is achieved in the soft tissues of blastrelated patients is unknown. However, with the release of cyto-kines and chemokines seen in blast related tissues,20 which arecapable of the stimulation of osteogenesis and the recruitmentof bone forming units, an inflammatory mediated cellular mech-anism is likely. Proinflammatory mediators, platelet derivedgrowth factors,21 fibroblast growth factors,22 transforminggrowth factor-β,23 insulin-like growth factor I24 and insulin-likegrowth factor–II,25 epidermal growth factors,26 and PGs27 haveall been implicated in osteoblast DNA synthesis and are presentin bone matrix. Analysis of wounds further details that certaininflammatory cytokines and chemokines were upregulated as aconsequence of high energy penetrating extremity wounds.Serum factors identified were IL-6, IL-10 and human monocytechemotactic protein-1. Wound effluent proteins upregulatedwere macrophage inflammatory protein-1α andinterferon-γ-inducible protein-10.28 This biochemical evidencesuggests that the formation of HO is associated with a systemicand localised hyperinflammatory response to the index injury.Laboratory manipulation of local and systemic cytokines havebeen proven to influence stem cell differentiation. Progenitorcells from muscle, periosteum and capillaries are capable of dif-ferentiation into osteoprogenitor cells thereby providing osteo-blast precursors in the generetaion of new bone.29 Furthermodulation of local stem cells is possible by the intrinsic nature

Table 1 Filter levels and elements

Filter Filter elements

Primary exclusions Audio-visualNewspaperLecturesBooksBiographies

Secondary exclusions LettersRetracted articlesCommentsEditorialsConference articles

Manual search/exclusions Anomalous articlesDuplicated articlesFOP/POHOPLL/DISH

DISH, diffuse idiopathic skeletal hyperostosis; FOP, fibrodysplasia ossificansprogressiva; OPLL, ossification of the posterior longitudinal ligament; POH,progressive osseous hyperplasia.

Figure 1 Heterotopic ossification in a transfemoral amputee.

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of the local tissue. It has been recently reported that a strictacidic environment is capable of reprogramming pluripotentcells from one cell lineage to another, thereby demonstratingbidirectional manipulation.30 31

Experimental models of heterotopic ossificationUrist reported an experimental model of new bone formationafter trauma in the 1930s.32 Prior to that Blessig published theossification of the kidney in response to ischaemia caused by

ligation of the renal artery in rabbits. Subsequently the identifi-cation, and isolation, of BMPs have allowed controlled osteoin-duction within animal soft tissue models.

Broadly speaking three basic models of HO formation arenow described33: Trauma-induced animal models; animalosteoinductive models (the interaction of native undifferentiatedcells and implanted BMPs) and osteogenetic cell transplantationmodels.

With the recognition that the formation of HO is related to ablast injury and amputation through the zone of injury, labora-tory experiments, including cellular and animal models, havebeen designed.34–36 A physiological model aims to combine allthree basic models of HO formation where the blast wavecauses localised injury and ischaemia, amputation results inrelease of mesenchymal stem cells residing in the bone canaland subsequent inflammation causing the release of inflamma-tory mediators, including BMPs. The heterogeneous events sur-rounding HO formation lead to experimental difficulties.Tannous reported good results from a Sprague-Dawley ratanimal model, however concerns lay in the delivery of the blast(water column) and relatively low survival rate.36

Elective surgery related heterotopic ossificationHip arthroplastyOver the last 50 years, total hip arthroplasty (THA) has becomeincreasingly common in the management of hip arthritis. The for-mation of HO post surgery is frequently noted20 and its incidencehas been reported to range from 8%37 to 90%.38 However,

Figure 2 A flow chart of the reviewprocess.

Table 2 Relevant article grouping

Relevant articles by group Filter elements

Elective surgery HipSpineShoulderElbow

Trauma surgery CivilianMilitaryBurnsTBI/SCIAmputations

Scientific basis of disease CellularAnimalHuman

TBI, traumatic brain injury.

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Brooker et al report the incidence of HO resulting in significantdisability is limited to those with high grades of HO and demon-strate, using their classification, that it is the final stage of ankylosis(Grade 4) that is most problematic for the patient.39 In the civiliansetting the principles of management of HO is that of primary pre-vention in higher risk patients. The recognised methods of preven-tion are the use of non-steroidal anti-inflammatory drugs, orcyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug, and radiation therapy.40

Heterotopic ossification prophylaxisA Cochrane Review, which included 16 Level 1 trials, demon-strated the benefit of regular indomethacin use during THAreporting a 59% reduction in the incidence of HO.40–42 Themechanism of action is via a combined effect of inhibition of

mesenchymal stem cells and the suppression of inflammation bythe inhibition of PG.43 However it was noted in these articlesthat the side effects of gastrointestinal ulcers and increased riskof postoperative bleeding were not benign. This has led to apreference for COX-2 inhibitors.

The inhibition of bone growth by radiation was establishedover 50 years ago.44 Doses in excess of 20 Grays resulted in thesuppression of vertebral growth in children. This has beenexploited in orthopaedics during THA.45 Preoperative or earlypostoperative local exposure of 7–8 Grays has been demon-strated to prevent the formation of HO45–47; however thetiming is relevant. By the 3rd postoperative day the mesenchy-mal stem cells have already differentiated, and treatment afterthis time is ineffective.48

Trauma related heterotopic ossificationCivilianPost-traumatic HO, traumatic myositis ossificans and myositis ossifi-cans circumspecta are all terms that have been used to define thesame problem—that of bone formation outside the skeletal systemfollowing trauma. In general the trauma in which HO is formedranges from muscle sprains and contusions through to open frac-tures of long bone.49 HO is seen in civilian, as well as military prac-tice; its formation is often subclinical and noted incidentally onradiographs. However, in particular during major trauma, the for-mation of HO may compromise rehabilitation if formed aroundlarge joints or dependent limbs. In the trauma environment, the lit-erature demonstrates that plastic surgeons have referenced, andinvestigated, that in patients with TBI and spinal cord injury (SCI),HO is a well-recognised phenomenon and its incidence ranges from10% to 20% of patients suffering a TBI and 20% to 30% ofpatients with SCI.50–52 Neurogenic HO (NHO) has been demon-strated to have a genetic element; the injury dictating the temporalrelation to its formation while the presence of HLA B27 identifyingthe population at risk of HO.53 The absence of HLA B27 does notpreclude the formation of NHO.53 HLA B27 is associated withinflammatory arthropathies such as ankylosing spondylitis and sero-negative spondyloarthropathies such as Reiter’s disease.54 Despitethe fact that a genetic predisposition is present, centrally released

Figure 3 Numbers of published articles on heterotopic ossification by year.

Figure 4 Biological prerequisites for heterotopic ossification.

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humoral factors previously described continue to be shown to drivebone formation.55

MilitaryHO has been described in history for over a 1000 years56; observedin amputees from the American Civil war,51 World War I2 and therecent conflicts in Iraq and Afghanistan.4 28 57–59 Contemporarymilitary operations have demonstrated an increased prevalenceof HO in military wounds, when compared with civiliancounterparts.4 51 52 The increase in its incidence from veteransserving in the US forces during Operation Iraqi Freedom andOperation Enduring Freedom has resulted in a renewed interestin HO and its extent documented in American and British mili-tary literature.4 9 The increased prevalence in recent conflictsmay be due to increased survivor rates due to enhanced bodyarmour, rapid medical care to the severely injured solider andsubsequent increased survivorship, as well as the mechanism ofinjury, particularly the IED. Specific wound related factors thatcorrelated with the development of HO included impairedhealing and bacterial colonisation.28 Disturbance of local micro-vasculature renders the soft tissues susceptible to HO formation.Localised changes in the arterial supply and reduced oxygentension render the soft tissues hypoxic and acidic. This favoursmineralisation and bone formation as the oxygen tension isrecovered through surgery or ventilation.60 61 The acidicenvironment may also be capable of modulating the cell lineagein soft tissues.30 31

In recent operations, the incidence of HO has been reported as60–64%.4 58 Box 1 details the factors that, demonstrated in a com-parative paper between the UK and USA, place the military casualtyat risk for the development of HO.4 It is likely that systematic andlocal factors come into play in the formation of HO (Figure 5).

Current and potential future military issuesWith amputees seen from operations in Afghanistan11 and a highrate of HO, rehabilitation may be compromised in this casualtygroup to a greater extent than previously seen. Significant disabil-ity has been reported in casualties from Vietnam with unilateraltransfemoral amputations and the majority of bilateral transfe-moral amputees in the Vietnam cohort abandoned their prosthe-tics and rely on a wheelchair for mobility; it was prosthetic relatedissues that led the patient abandoning a prosthetic.3 62

The current management of HO is restricted to operativeexcision in symptomatic patients who have failed non-operativemanagement such as rest, adjustment of pain medication,selected injections, and nerve ablation of neuromas, socketmodification and physiotherapy.10 63 Separately publishedBritish and American military experience in surgical excisionappears similar.58 63 Multiple centres in the UK and the USA

report the necessity of primary excision of symptomatic HOwithin the 1st year after injury, combined with indomethacin orCOX-2 use. Good functional outcome and no significant recur-rence at 12 months after surgery with this approach are seen.59

Additionally, British Plastic and Reconstructive surgeons at theRoyal Centre of Defence Medicine described a technique ofserial operations to elevate, protect or excise overlying skin andsoft tissues to improve the weight bearing surface.63

REQUIRED RESEARCHAnimal heterotopic ossification modelHO formation in rodents has been achieved but included cyto-kine modulation of the animal.35 The model produced byTannous et al used local blast to the lower limb and thereforesystemic causes of blast related HO were not taken intoaccount.36 However, Alfieri et al describe ongoing work atWalter Reed National Military Medical Center, of a reliablereproducible systemic blast model with open fractures, woundischaemia, a large zone of injury, an appropriate bioburden andamputations through the zone of injury.58 The required experi-mental animal model for HO formation is a complex one.However, a reliable small animal model requires validation andto be expanded to larger species. Once established, individualvariables, such as blast magnitude and morphology, infection,

Figure 5 Interaction of local and systemic factors in the formation ofheterotopic ossification.

Box 1 Casualty factors leading to increased risk ofheterotopic ossification (HO)4

▸ Age▸ Blast mechanism of injury (MOI)▸ Zone of injury (ZOI) and subsequent amputation▸ Injury severity score >16▸ Topical negative pressure (TNP) dressings▸ Traumatic brain injury (TBI)▸ Multiple extremity injuries▸ Number of debridements before closure

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surgical debridement zones and local biomechanics, can bemanipulated to help in the prevention and management of HO.

Cellular levelTo date a reliable cellular model of HO formation secondary toblast has yet to be published. Detailed structural evaluation isstill lacking in the literature. Limited imaging techniques aredescribed, however, detailed structure of the cortex and lamellarconfiguration of HO, in comparison with normal bone, is yet tobe seen. This would also provide control data to samplesretrieved from experimental models.

Military aetiological factorsThe comparative study by Brown et al showed significant simi-larities between the UK and US experiences of wounds and sub-sequent HO formation in Iraq and the early years inAfghanistan.4 However, the UK data set only included casualtiesup to 2008. It is well recognised that the modus operandi of theTaliban and insurgents changed at this time to the use of IEDsof greater magnitude.

Muscle ischaemia and necrosis are believed to be related toHO formation.64 Therefore tourniquet related data requirescomparison in these subjects and larger subject numbers arerequired to further evaluate the link to topical negative dressingsand HO, that was noted previously.4

Management of HO in military populationMilitary amputees requiring surgery for wound and residuumrelated problems during rehabilitation, such as those seen inlimbs complicated by HO, are referred from their rehabilitationcentre to secondary care specialists for surgical managementthroughout the UK. This provides an opportunity for data ana-lysis on protocols used and complication/recurrence rates afterHO surgery at different centres. Ideally a prospective cohortstudy in the use of medical and surgical strategies in manage-ment of HO should be considered. However, a retrospectivecomparative multiarm case series would give direction to futureresearch. The timing of HO excision may be the key; as detailedpreviously, surgery is contemplated when rehabilitation is com-promised. However, once risk stratification is analysed, andwhen HO can be clinically recognised early in its development,surgery may be expedited to prevent rehabilitation delays.

CONCLUSIONIt is likely that HO will continue to compromise the rehabilita-tion and long-term outcome of the cohort of traumatic ampu-tees from operations in Afghanistan, the magnitude of which,while at present is unknown, is likely to reflect the experience inIraq and the early stages of Afghanistan. As noted, there remainsignificant gaps in the understanding of this condition. Work isrequired in this field to fully understand its pathogenesis fromthe triggering traumatic event, cellular inception to primary pre-vention. Understanding the key to unlocking its formation islikely to help its prevention and/or subsequent management.

Contributors DSE: main researcher and author. JCC: research supervisor andguarantor.

Competing interests None.

Provenance and peer review Not commissioned; externally peer reviewed.

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